Valsartan is a potent, orally active nonpeptide tetrazole derivative that selectively inhibits angiotensin II receptor type 1. By blocking the action of angiotensin, valsartan causes reduction in blood pressure and is therefore used in treatment of hypertension, congestive heart failure and post-myocardial infarction. Valsartan also known as (S)—N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl] methyl]-L-valine or N-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-N-valeryl-L-valine, has the following structure and is marketed as the free acid under the name DIOVAN.

DIOVAN is prescribed as immediate release oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg of valsartan.
The quality and safety of pharmaceuticals can be significantly affected by the presence of impurities. Consequently, testing and controlling generation of impurities in the active pharmaceutical ingredient (API) during synthesis and in the pharmaceutical product during manufacture becomes imperative. Likewise, the presence of impurities in valsartan formulation may affect its safety and shelf life. USP monograph for valsartan describes two liquid chromatographic determinations for limiting a total of three related compounds, valsartan related compounds A, B and C. Valsartan related compound A having the following structure, is the R-enantiomer of valsartan and is chemically known as (R)—N-valeryl-N-([2′-(1H-tetrazole-5-yl) biphen-4-yl] methyl)-valine. It is generated by isomerization of valsartan S-isomer and is commonly referred to as Impurity A.

Various attempts have been made to control the levels of valsartan R-isomer impurity in valsartan during synthesis and provide an enantiomeric excess of S-valsartan. U.S. Pat. No. 7,728,021 and US2006/0281891 discuss processes for obtaining valsartan in substantially pure enantiomeric form. Though attempts have been made to provide valsartan API with an enantiomeric excess of S-isomer, not many attempts have been made to control generation of valsartan impurity A during the preparation of pharmaceutical formulations. WO2009/135646 discusses an immediate release formulation of valsartan wherein filler such as solid sugar alcohol consisting of mannitol, xylitol, maltitol, sorbitol, lactitol, erythritol, isomalt and mixtures thereof is employed. The solid sugar alcohols have been discussed to shorten the wet granulation process because less drying time is needed to achieve a residual humidity suitable for tabletting and thereby provide formulations with an impurity profile which is better since tablets are for less time under stressful conditions.
However, attempts have not been made to control the levels of impurity A in controlled release pharmaceutical formulations of valsartan.
The absolute bioavailability of valsartan is about 25%. Pharmaceutically active agents which exhibit low bioavailability unfortunately create a need for frequent dosing of a large amount of the active agent in order to provide and maintain therapeutic levels. The need for frequent dosing presents patient compliance problems. Attempts have therefore been made to deliver valsartan in an extended release form. Further, since the relatively low bioavailability of valsartan is primarily due to its poor solubility in the acid milieu of the stomach, attempts have been made to improve the bioavailability of valsartan by incorporation of solubilizers in the formulations.
WO2009/084040 discusses controlled release once a day formulation of valsartan in the form of a gastroretentive dosage form comprising solubilized active agent. Such formulations however have been identified to have increased levels of impurity A which is not desirable. Incorporation of solubilizers to improve the solubility and bioavailability of valsartan necessitates treating valsartan with solubilizers by different methods and at different temperature and time conditions. Such treatments tend to result in the generation of impurity A in the formulations, thereby presenting a need to monitor and control valsartan R-isomer impurity when preparing extended release pharmaceutical formulations, particularly extended release formulations comprising solubilizers.
The present inventors after rigorous studies provide extended release formulations of valsartan which are substantially free of valsartan R-isomer. The present inventors provide extended release formulations comprising valsartan, at least one solubilizer, at least one release modifier and at least one pharmaceutically acceptable excipient; wherein valsartan is completely or partially solubilized with the solubilizer at controlled solubilization conditions to provide formulations which are substantially free of valsartan R-isomer.